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Juvenile-onset chronic arthritis
Juvenile-Onset
Chronic Arthritis
Clinical and Roentgenographic Subset
FRANK C. ARNElT, M.D.* WILMA B. BIAS, Ph.D. MARY BETTY STEVENS, M.D. Baltimore, Maryland
From The Rheumatology Division and Immunogenetics Laboratory, Department of Medicine, The Johns Hopkins University School of Medicine and Hospital, and The Good Samaritan Hospital, Baltimore, Maryland. This study was supported by OPD-CRC Grant 5MOlRROO722-07 and a multipurpose Arthritis Center Grant lP60AM20558-01. Requests for reprints should be addressed to Dr. Frank C. Arnett, The Good Samaritan Hospital, 5601 Loch Raven Boulevard. Baltimore, Maryland 21239. Manuscript accepted March 2.1980. * Clinical Scholar of the Arthritic Foundation.
Features of a Unique HLA-B27
Previous studies of HI&B27 in children with juvenile-onset chronic arthritis have shown an association in boys with pauciarticular disease which may progress to ankylosing spondylitis. The spectrum of B27-associated disease, however, especially as it relates to arthritis persisting into adulthood, has not been fully clarified. Thus, clinical, roentgenographic, serologic and immunogenetic studies were performed in 54 patients (39 adults and 15 children) with persistent juvenile-onset chronic arthritis. All had had the onset of disease in peripheral or axial joints, and patients with typical febrile Still’s disease were excluded. Thirty-five patients (65 percent) were seronegative for both rheumatoid factor and antinuclear antibodies. HLA-B27 (BJT)was present in 20 of these 35 seronegative patients (54 percent) (p < 0.005) Four of the 20 (20 percent) had an axial onset and typical ankylosing spondylitis. Peripheral arthritis, however, dominated the course of the remaining 16 patients who had the B27 antigen. Polyarticular disease (nine patients) with “rheumatoid-like” hand deformities (eight patients) occurred primarily in female patients. In addition, sacroiliitis or spondylitis occurred in 14 and acute iritis in five. Cervical apophyseal joint fusion, especially at the level of the C2-C3, a lesion previously ascribed to juvenile rheumatoid disease, was common i@seronegative patients a:d correlated with the presence of B27 (p < 0.01) and sacroiliitis (p < 0.0005). These data suggest that the presence of B27 may mark a group of young women with a dominant peripheral and cervical spondylitic syndrome, often beginning in childhood, which mimics rheumatoid arthritis. Determining the absence or presence of the B27 antigen may be a useful test in the proper diagnosis and classification of such patients. Juvenile-onset chronic arthritis, also termed juvenile rheumatoid arthritis, is now believed to represent more than one distinct disease entity [l-4]. The diversity of dlinical presentations, patterns of articular involvement, extra-articular features and the presence or absence of rheumatoid factors (RF] and antinuclear antibodies [ANA], strongly suggest a heterogeneous group of rheumatic diseases [l-4,5,6]. The association of certain histocompatibility (HLA) antigens with different clinical subsets adds evidence of genetic heterogeneity as well [7-111. Previous studies of children have demonstrated a high frequency of HLA-B27 in boys with oligo- or pauciarticular-onset in whom more classic signs of ankylosing spondylitis may later develop [8-lo]. There are, however, few studies of adults whose disease has persisted since
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JUVENILE-ONSET CHRONIC ARTHRITIS-ARNETT
TABLE I
TABLE III
Patients with Juvenile-Onset Chronic Arthritis Classified with Respect to Serologic Markers and HLA-B27 Total
Groups Group A = B = Group A = B =
ET AL.
Patients (no.) Adults 24
35
I, Seronegative HLA-B27 positive HLA-527 negative II, Seropositive RF with or without ANA ANA alone
(20)’ (W 19
15
(12) (7)
(4) (71 4 (2) (2)
(10) (5)
39
54
TOW
Children 11
(16) (8)
15
NOTE RF = rheumatoid factor; ANA = antinuclear antibodies. l p < 0.005 for comparison of B27 in seronegative versus sero-
positive patients.
childhood to determine how the B27 antigen may influence future expression of disease. Thus, a systematic clinical, serologic and roentgenographic review coupled with HLA typing was initiated in our patients with juvenile-onset chronic arthritis, both adults and children. In this report we describe the unique clinical and roentgenographic features in these patients, many heretofore diagnosed as having rheumatoid arthritis, who appear to have a B27-associated disease. MATERIALS AND ME~ODS Patient Selection. All patients, children or adults, with a diagnosis of juvenile rheumatoid,arthritis or juvenile-onset chronic arthritis evaluated by members of this adult rheumatology division between fuly 1.1974 and December 3X1978, were reviewed per protocol. Definitions were those suggested by the JRA Criteria Subcommittee of the American Rheuma-
TABLE II
Ages of Onset, Ag& at Evaluation and Disease Duration in Patients with JuvenileOnset Chronic Arthritis I
ASeM Onset
No. GroupI, Seronegative A = B27 positive Range Mean B = 827 negative Range Mean
Group It, Seropodtlve A = RF positive Range Mean B = ANA positive Range Mean
lyr)
Ageat &sass EvaluationDuration (Yr) (Yr)
35 (20) 3-16 11.0
11-62 29.7 ’
l-52 18.7
3-16 11.3
6-38 20.2
0.25-29 10.9
4-10 10.3
9-72 19.1
0.75-58 8.8
3-16 8.2
7-38 17.6
0.5-27 9.3
(16)
19 (12)
(7)
NOTE: RF = rheumatoid factor; ANA = antinuclear antibodies.
370
Pattern of Peripheral Joint Onset of Juvenile Chronfc Arthritis by Sex
September 1980 The American Journal of Medicine
Group I, Seronegative A = B27-positive Female Male B = B27-negative Female Male Group II, Seropositlve A = RF-positive Female Male B = ANA-positive Female Male
Patients (no.1
Polyarticular’ onsst flKLf
Pauciarttculait met ino.)
10 lot
7 2
3 4
12 3
8 0
4 3
9 3
8 3
1 0
5 2
0 0
5 2
NOTE: RF = rheumatoid factor; ANA = antinuclear antibodies. l Greater than four joints affected. f Four or fewer joints affected. t Four of these B27positive males had onset in the low back rather than peripheral arthritis.
tism Association [12.13] and included (I) persistent arthritis in one or more peripheral joints for at least three months; (2)onset at age 16 or under; and (3) exclusions of other causes of arthritis in children. No attempt was made, however, to exclude juveniles whose disease had begun as an exclusively axial arthropathy and progressed to typical a&losing spondylitis (four patients]. On the other hand, patients with a typical clinical picture of the acute febrile form of juvenile rheumatoid arthritis (Still’s disease) were not included in this study [5,6,14,15]. Eight such patients were seen over the same time interval, but none had a persistent arthritis, only one had evidence of destructive changes on roentgenograms (bilateral fusion of the wrists), and previous studies have shown no association of B27 with this group [7-191. Patients were selected without regard to the presence or absence of rheumatoid factor, ANA or HLA-B27. Clinical records and roentgenograms were reviewed, and patients were recalled for study when data were incomplete. All had complete histories and physical examinations, roentgenograms of symptomatic or abnormal joints and tests for RF and ANA. HLA typing was performed in all but those who had RF, since previous studies have shown no B27 association with this group [7-lo].
Subclassification into Patient Groups. Group I-Patients seronegative for RF and ANA: A, HLA-B27 positive; B, HLA-B27 negative. Group II-Patients seropositive for A, RF with or without concomitant ANA; B, ANA alone. The pattern of onset was defined as polyarticular if greater than four joints were involved over the first six months of illness, and pauciarticular if four or fewer joints were affected, as previously suggested by Brewer et al. [X3]. Roentgenographic Methods. All patients with symptomatic cervical spine disease had lateral extension and flexion views to assess apophyseal joint fusion and subluxation of the first
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JUVENILE-ONSET CHRONIC ARTHRITIS-ARNETT
TABLE IV
ET AL.
Roentgenographic and Extra-artlcular Flndings in Patients with Juvenile-Onset Chronic Arthrltls
Roantgenographk Features Carvkal
Extra-artkular Features
No.
‘%A-like” Hands
Apophyseal Fuslon’
Cl-C2 Subluxation+
SI or sPondyll8s*
Heel PaIn
Acul lrlllsI
Chronic lrllls#
20 15
6 3
10 3
1 0
14 1
6 2
5 0
0 0
0 0
6 3
12 7
8 1
0 0
6 0
0 0
0 0
0 0
0 3
5 0
2 0
RA Nodules**
Mlcro9. nalhla++
Group I, Seronegatlve A = B = Group A = B =
B27-positive B27-negative II, Seroposltlve RF-positive ANA-positive
NOT’&: SI = sacroiliitis; RF = rheumatoid factor; ANA = antinuclear antibodies; RA = rheumatoid. p< 0.01 for association with 827. + p 5 0.0001 for association with RF. g p 5 0.0001 for association with 827. 5Ii p 5 0.01 for association with B27. p 5 0.01 for association with 827. # p
l
and second cervical vertebrae. If anteroposterior films of the pelvis suggested sacroiliac disease, additional Ferguson or oblique views of the sacroiliac joints were obtained and graded by New York Criteria (161. Only those with grade 3 or 4 disease were considered to have definite sacroiliitis. Laboratory Methods. The RF content was determined by a standard latex fixation method 1171and was considered present if the titer exceeded l/160. ANA were assessed utilizing the method of Holborow et al. [la] with mouse liver as substrate. HLA typing for A, B and C locus antigens was performed with a standard microcytotoxicity test [19]. Statistical Methods. Chi-square with Yates’ correction was used for all statistical correlations. Because the presence or absence of HLA-B27 was not determined in the patients with RF, all comparisons with B27 were performed under the assumption that these patients did not have the B27 antigen. In addition, significant associations were retested assuming a normal population frequency of 10 percent for B27 in the group
TABLE V
RESULTS A total of 54 patients was studied, 39 (72 percent] had reached adulthood, whereas 15 (28 percent) were still children. The number of patients in the predefined seronegative or seropositive groups is shown in Table I. HLA-B27 was present in 20 of the 35 (57 percent) seronegative patients (p < 0.005), 16 of whom were adults and four children (Table I]. One of the seven patients with ANA alone (group II, B) had B27. Patients with RF (group II, A] were not studied for B27. Among the 15 seronegative patients without B27, four (27 percent) had B7, an immunologically cross-reactive specificity with B27 [20] (p = NS), and four (27 percent) had BW38, an antigen found in 2 percent of our 1,000
Clinical and Roentgenographlc Characteristics of Cervical Spine Involvement In Patient Groups with Juvenile-Onset Chronic Arthritis
Csrvlcal Pain (no.)
Llmllsd CWVhXl Mo8on (M
20 15
11 (55)
12 (60)’
6 (40)
3 (20)
12 7
9 (15) 0
1 (6)§ 011
Patients (no.) Group A = B = Group A = B =
with RF. If both comparisons did not yield a value of p ? 11.05, no significance was ascribed.
I, Seronegatlve B27-positive B27-negative II, Seroposltlve RF-positive ANA-positive
FuslonC2-C3 Alone (no.)
FU8fOll C2-C3 and/or Below (no.)
4 (20)+$
6 (30)+*
2 (13)
1 (7)
1 (5) 0
0 0
0 0
6 (50) 0
Cl-C2 SUblUX-
aliom (no.)
NOT&: RF = rheumatoid factor; ANA = antinuclear antibodies. Figures in parentheses are percents. p 5 0.05 for association of limited cervical motion with 827 versus non-B27 seronegative patients. t p < 0.0005 for association between fusion of C2-C3 and/or below with limited cervical motion. $ p < 0.01 for association between fusion of C2-C3 and/or below with B27. 8 p 5 0.01 for association of limited cervical motion with 827 versus RF-positive patients. 1’p < 0.01 for association of limited cervical motion with 827 versus ANA-positive patients. l
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ET AL.
Figure 1. Roentgenograms of hand showing rheumatoid-like deformities in a 54 year old woman with onset at age 16. This patient now has complete spinal fusion and HLA-B27 (group I, A).
normal controls (corrected p < O.OOS),which is also associated with psoriatic arthritis [Zl]. None had psoriatic skin lesions. The ages of onset among the groups were similar (Table II). Forty-four patients (81 percent) were white and nine were black, only two of whom had the B27 antigen. One additional oriental patient had the B27 antigen. Sex and Pattern of Onset. There was a striking predominance of females in all groups (Table III], except for the equal sex distribution in those with the B27 antigen (B27-positives, group I, A]. Furthermore, a polyarticular mode of onset was most common in the
B27-positive females (seven of 10). Of the 10 B27-positive males, only two had a polyarticular onset whereas four had pauciarticular disease; four males had only an axial presentation [low back pain]. In the B27-negative and RF-positive groups, a polyarticular onset was most common, whereas all patients with ANA alone (group II, B) had pauciarticular disease. Clinical and Roentgenographic Features. The major clinical and roentgenographic findings among these groups are shown in Table IV. The B27-positive patients seemed to cluster together with certain unique articular and extraarticular manifestations.
Figure 2. Roentgenogram showing lateral flexion of the cervical spine in a young woman with 827 and peripheral arthritis showing fusion of the apophyseal joint between segments of the second and third cervical vertebrae (group I, A).
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A destructive peripheral polyarthritis, clinically and roentgenographically indistinguishable from rheumatoid arthritis, occurred in eight patients (six females and two males]. Symmetrical involvement of the small joints of the hands with flexion deformities of digits and fusion of wrists was prominent (Figure 1). The clinical character and roentgenographic appearance of cervical spine involvement also seemed to distinguish certain groups (Table V). Neck pain was common in both seronegative and seropositive patients; however, significant limitation of cervical extension and rotation was more common in B27-positive patients (60 percent] when compared to those w/th RF (8 percent] (p < 0.01) and ANA (0 percent] (p < 0.01). Roetgenograms of the cervical spine were available and reviewed in 51(94 percent) of the patients. Roentgenographically, fusion of cervical apophyseal joints was associated with limitation of neck motion (p < 0.0005] and with B27 (p < 0.01). Fusion between the second and third cervical vertebrae alone (Figure z), or in combination with lower segments (Figure 3)-lesions frequently ascribed to juvenile rheumatoid disease-occurred in 10 patients with B27. On the other hand, subluxation of the first and second cervical vertebrae-a lesion common to adult rheumatoid arthritis-occurred in six (50 percent] of those with RF (p ‘T 0.0001). Interestingly, of the three B27-negative patients (group I, B) with cervical spondylitis, Crohn’s disease developed in one 10 years after the onset of arthritis and another had HLA-BW38, an antigen associated with psoriatic arthritis [21]. Sacroiliitis was found in 14 B27-positive patients (six women and eight men], in six of whom (five men and one woman) syndesmophytes in lumbar and thoracic regions (spondylitis] had developed (Table IV]. Four of these patients denied having any symptoms of back pain. The presence of cervical apophyseal fusion correlated strongly with lower axial skeletal involvement (p <0.0005) (Table IV]. Heel pain with roentgenographic evidence of calcaneal periosititis was present in eight patients (40 percent] with B27 (p ‘T 0.011, whereas two seronegative, B27-negative patients had heel pain without any abnormality noted on roentgenograms (Table IV]. The type of inflammatory ocular disease (iritis) also segregated by laboratory marker (Table IV). Five B27-positive patients had had multiple episodes of acute iritis which had resulted in significant visual loss in two. Besides the correlation with B27 (p 7 O.Ol), this form of ocular disease was also associated with sacroiliitis (p 0.005). Conversely, an insidious chronic iridocyclitis resulting in visual loss occurred in three patients seropositive only for ANA (group II, B) (p 7 0.0005). A recessed mandible or micrognathia, a hallmark of juvenile arthritis, although most common in the B27 group did not statistically correlate with this marker (Table IV). Similarly, no relation to age of onset or temporomandibular joint symptoms could be found,
CHRONIC
ARTHRITIS-ARNETT
ET AL.
Figure 3. Roentgenogram showing lateral flexion of the cervical spine showing fusion of all apophyseal joints. The patient had onset of arthritis at age three and Crohn’s disease developed 10 years later. HLA-627 was absent (group I, 6).
although there was a correlation with polyarticular onset (p < 0.001). Instead, this abnormality of growth was associated with cervical apophyseal joint fusion (p < 0.01). No patients with subluxation of the first and second cervical vertebrae had micrognathia. Rheumatoid nodules were present only in five patients (10 percent), all of whom had RF (group II, A) (p < 0.0005). Comparisons with Adult-Onset Spondylitis. Because these B27-positive patients, especially the women, appeared to have an atypical spondylitic syndrome, a review of our adult patients with spondylitis was undertaken. Seven of 61 patients had been classified as having atypical spondylitis because of severe peripheral or cervical arthritis or both [Table VI). The peripheral arthritis in these predominantly young white women frequently mimicked or was diagnosed as rheumatoid arthritis despite the absence of RF. Equally striking was the finding of cervical apophyseal joint fusion indis-
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TABLE VI
Patient 1
2
CHRONIC
ARTHRITIS-ARNETT
ET AL.
Adults with Atypical Spondylitic Syndromes Characterized by Prominent Peripheral Arthritis, Cervical Spondylitis or Both, Similar to Juvenile-Onset Chronic Arthritis Associated with HLA-B27
Race and Sex
Age at Onset (vr)
Disease Duration (yr)
23
4
W,F
WI
25
22
3
WS
20
1
4
W,F
37
10
5
WS
39
3
6
W.F
27
25
7
W,M
39
3
Peripheral Joints Involved PIPS, MCPs, Ws, KS, Es, Ss, MTPs, TMJs PIPS, Ws, KS PIPS, MCPS, ws, Es, Ss, KS, As PIPS, ws
Cervical Pain Reslr
+
+
Cervical Spondylitis (level)
+
Low Back Pain Restr
-
Sacroiliitls
HLA027
+
+
C2-C3
+
+
+
+
+
+
+
+
-
C2-C5 -
+
-
-
+
+
+
+
+
-
+
-
-
-
-
-
+
+
+
+
+
-
+
+
None
+
+
PIPS. MCPs, Ws, KS, As, MTPs PIPS, MCPs, Ws, Ss, KS, As, MTPs
+
-
C2-C4 + C2-C4 -
+
-
-
NOTE: Restr = restriction; PIPS = proximal interphalangeal joints; MCPs = metacarpalphalangeal joints; Ws = wrists; KS = knees; Es = elbows; Ss = shoulders, As = ankles; MTPs = metatarsal phalangeal joints; TMJs = temporomandibular joints. C2 = second cervical vertebra; _ C3 = third cervical vertebra; C4 = fourth cervical vertebra.
tinguishable from that found in the patients with juvenile-onset chronic arthritis. HLA-B27 was present in five (71 percent]. COMMENTS Juvenile-onset chronic arthritis is a generic diagnostic term recently suggested because of the realization that juvenile rheumatoid arthritis was not one disease entity [l]. Earlier subclassifications of juvenile rheumatoid arthritis had reflected this suspected clinical heterogeneity in that they were based on different modes of presentation [Z&23]. The application of serologic markers appeared to further define subgroups. RF was most commonly found in those with polyarticular-onset, rheumatoid nodules and a bad prognosis [24-261, whereas ANA marked a group of girls with pauciarticular disease at risk for chronic iridocyclitis [27]. The genetic marker, HLA-B27, known to be strongly associated with ankylosing spondylitis and Reiter’s syndrome [28-311, was also found in 26 to 42 percent of the patients with juvenile-onset chronic arthritis [~-IO]. Those with B27 were most commonly boys with pauciarticular involvement in whom sacroiliitis or even ankylosing spondylitis later developed. It is noteworthy that in several of these series [7,9,10] there were small numbers of patients, including girls, with B27 and a polyarticular onset. Because the frequency of B27, although slightly increased over normal population frequencies, did not reach statistical significance, it could not be confidently associated with the disease process. The present study in an adult rheumatology setting focused primarily on adults who still required medical
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surveillance for a juvenile-onset chronic arthritis, often after many years. Of the 20 patients with B27-positivity, four men (20 percent) had a lower axial onset with progression to typical ankylosing spondylitis. The remaining 16 patients, however, had all presented with peripheral arthritis which persisted and was polyarticular in the majority, especially women (seven females, two males). The reason for this apparent change in disease spectrum with time is not entirely clear. It is possible, however, that many of the boys with earlier disease had shown improvement and no longer sought medical care, or had been reclassified when more typical ankylosing spondylitis became apparent. The girls, on the other hand, continued to have persistent peripheral arthritis, and the diagnosis of juvenile rheumatoid arthritis was apparently never questioned or re-examined. The validity of these observations is supported by a similar study of “juvenile rheumatoid arthritis persisting into adulthood” performed over a decade ago which also documented a high frequency of women with seronegative peripheral, cervical and low back arthritis [32]. HLA-B27 was unknown at that time and could not be applied. The majority of our B27-positive patients with childhood-onset peripheral arthritis, as well as a group of patients with adult-onset disease with similar features, were white women with a dominant peripheral and cervical articular syndrome. A deforming and destructive peripheral polyarthritis affecting in symmetric fashion the small joints of the hands and wrists and frequently other joints, clinically mimicked adult rheumatoid disease, except for the absence of nodules and RF. Lower axial skeletal complaints, although fre-
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quently present, seemed to be overshadowed by peripheral disease. Nonetheless, sacroiliitis or spondylitis was present roentgenographically in the majority. Of special interest was the type of cervical spine involvement which differed between the groups. Fusion of the apophyseal joints between segments of the second and third cervical vertebrae or below has been considered a hallmark of juvenile rheumatoid arthritis [33-361, whereas subluxation of the first cervical vertebrae on the second cervical vertebra is commonly seen in adult patients with seropositive rheumatoid arthritis [37-381. This study demonstrates that cervical apophyseal fusion is strongly associated with B27, seronegativity and sacroiliitis-all features of spondylitic rather than rheumatoid disease. On the other hand, children with RF-positive arthritis appear more likely to have subluxation of the first and second cervical vertebrae like their counterparts with adult-onset disease. Micrognathia is another well-recognized complication of juvenile rheumatoid arthritis; however, the reasons for growth retardation of the mandible remain unclear. Calabro et al. [6] have stated that it may relate to cervical spine disease, whereas other studies [39] do not confirm this impression. In the present series, micrognathia did not correlate with cervical spine disease in general, or with subluxation of the first and second
ET AL.
cervical vertebrae. There was, however, a strong association with a more specific cervical abnormality, namely, cervical apophyseal fusion. The reasons for describing these patients transcend the need to clarify disease classification. Juvenile rheumatoid arthritis is clearly a misnomer in the majority of patients with a childhood-onset chronic arthritis. The use of this diagnostic label may promote inaccurate prognostication and dictate therapy which is ineffectual, hazardous or both. In addition, in patients with spondylitis certain unique articular and extrarticular complications often develop which might go unrecognized or be inappropriately treated. Furthermore, these data support the existence of a unique form of spondylitis, usually affecting children or young adult women, in which peripheral and cervical involvement dominates the clinical picture [40-421. Roentgenographic attention to the cervical as well as the lower spine may improve diagnosis of these patients. Finally, determination of HLA-B27 in seronegative childhood-onset arthritis, regardless of the patient’s sex or number of involved joints, may provide a useful diagnostic aid. It must be emphasized, however, that proper interpretation of a positive B27 test depends upon a comprehensive clinical evaluation and, in some patients, a watchful period of time.
REFERENCES 1. Ansell BM: Chronic arthritis in childhood. Ann Rheum Dis 1978; 37: 107. 2. Schaller JG: Juvenile rheumatoid arthritis. I. Arthritis Rheum 1977; 20 (suppl2): 165. 3. Ansell BM: Juvenile chronic polyarthritis. III. Arthritis Rheum 1977; 20 (suppl2): 176. 4. Schaller JG: The diversity of JRA. A 1976 look at the subnrouus of chronic childhood arthritis. Arthritis Rheum 197?; 20.(suppl6): 52. 5. Calbro JJ. Katz RM, Maltz BA: A critical reappraisal of juvenile rheumatoid arthritis. Clin Orthop 1971; 74: 101. 6. Calabro JJ, Holgerson WB, Sonpal GM, Khoury MI: Juvenile rheumatoid arthritis: a general review and report of 100 patients observed for 15 years. Semin Arthritis Rheum 1976; 5: 257. 7. Rachelefsky GS, Terasaki PI, Katz R. Stiehm ER: Increased prevalence of W27 in juvenile rheumatoid arthritis. N Engl J Med 1974; 290: 892. 8. Edmonds J, Morris RI, Metzger AL, et al.: Follow-up study of juvenile chronic polyarthritis with particular reference to histocompatibility antigen W27. Ann Rheum Dis 1974: 33: 289. 9. Schaller JG, Ochs HD, Thomas ED, Nisperos B, Feigl P, Wedgwood RJ: Histocompatibility antigens in childhoodonset arthritis. J Pediatr 1976; 88: 926. 10. Veys EM, Coigne E, Mielants H, Verbruggen A: HLA and juvenile chronic arthritis. Tissue Antigens 1976; 8: 61. 11. Stastny P. Fink CW: Different HLA-D associations in adult and juvenile rheumatoid arthritis. J Clin Invest 1979; 63: 124. 12. Brewer EJ, Bass JC. Cassidy JT, et al.: Criteria for classification of juvenile rheumatoid arthritis. Bull Rheum Dis 1973; 23: 712. 13. Brewer EJ, Bass JC, Baum J, et al.: Current proposed revision of JRA criteria. Arthritis Rheum 1977; 20 (suppl2): 195. 14. Still GF: On a form of chronic joint disease in children. Med
Chir Trans 1897; 80: 1. 15. Baum J, Baum ER: George Frederic Still and his account of childhood arthritis-a reappraisal. Am J Dis Child 1978; 132: 192. 16. Gofton JP: Report from the subcommittee on diagnostic criteria for ankylosing spondylitis. In: Bennet RH, Wood PNH. ed. Ponulation studies of the rheumatic diseases. Amsterdam: Bxcerpta Medica Foundation, 1968; 456. 17. Sinner IM. Plotz CM: The latex fixation test. I. ADDlication tothe serologic diagnosis of rheumatoid arthritis. ‘Am J Med 1956; 21: 888. 18. Holborow EJ, Weir DM, Johnson GD: A serum factor in lupus erythematosus with affinitv for tissue nuclei. Br Med 11957: 2: -732. 19. Amos DB, Bashir H, Boyle W, MacQueen M, Tiilikainen A: A simple microcytotoxicity test. Transplantation 1969; 7: 220. 20. Arnett FC. Hochbere MC. Bias WB: Cross-reactive HLA antigens in B27-negitive Reiter’s syndrome and sacroiliitis. Johns Hopkins Med J 1977; 141: 193. 21. Espinoza LR, Vasey FB, Oh JH, Wilkinson R, Osterland CK: Association between HLA-BW38 and peripheral psoriatic _ arthritis. Arthritis Rheum 1978; 21: 72.. _ 22. Calabro JJ, Marchesano JM: Juvenile rheumatoid arthritis. N Engl J Med 1967; 277: 696,746. 23. Bywaters EGL: Categorization in medicine: a survey of Still’s disease. Ann Rheum Dis 1966: 26: 185. 24. Bianco NE, Panush RS, Stillman JS, Schur PH: Immunologic studies of juvenile rheumatoid arthritis. Arthritis Rheum 1971;14:685. 25. Schaller J, Wedgewood
RJ: Juvenile rheumatoid arthritis: a review. Pediatrics 1972; 50: 940. 26. Goel KM, Shanks RA: Follow-up study of 100 cases of juvenile rheumatoid arthritis. Ann Rheum Dis 1974; 33:25. 27. Schaller JG, Johnson GD, Holborow EJ, Ansell BM, Smiley WK: The association of antinuclear antibodies with the
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28. 29. 30. 31. 32. 33. 34.
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ET AL.
chronic iridocyclitis of Juvenile rheumatoid arthritis (Still’s disease). Arthritis Rheum 1974; 17: 409. Brewerton DA, Caffrey M, Hart FD, James DCO, Nicholls A, Sturrock RD: A&losing spondylitis and HL-A 27. Lancet 1973; 1: 904. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl Med 1973; 288: 704. Brewerton DA, Niche 1Is A, Oates JK, Caffrey M, Walters D, James DCO: Reiter’s disease and HL-A 27. Lancet 1973; 2: 996. McClusky OE. Lordon RE, Arnett FC: HL-A 27 in Reiter’s syndrome and psoriatic arthritis. A genetic factor in disease susceptibility and expression. J Rheum 1974; 1: 263. Jeremy R, Schaller J. Arkless R, Wedgewood RJ. Healey LA: Juvenile rheumatoid arthritis persisting into adulthood. Am J Med 1968; 45: 419. Coss JA. Boots RH: Juvenile rheumatoid arthritis: a study of 56 cases with a note on skeletal changes. J Pediatr 1946; 29: 143. Martel W, Holt JF, Cassidy JT: Roentgenologic manifestations of juvenile rheumatoid arthritis. Am J Roentgen01 1962; 88:
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400. 35. Ziff M, Contreras V, McEwen C: Spondylitis in post-pubertal oatients with rheumatoid arthritis of iuvenile onset. Ann kheum Dis 1956; 15: 40. 36. Cassidy JT, Martel W: Juvenile rheumatoid arthritis: clinicoradiologic correlations. Arthritis Rheum 1977; 20 (suppl 2): 207. 37. Sharp J, Purser DW, Lawrence JS: Rheumatoid arthritis of the cervical spine in the adult. Ann Rheum Dis 1958: 17: 303. 38. Bland JH: Rheumatoid arthritis of the cervical spine. J Rheum 1974; 1: 319. 39. Levinson JE, Balz GP, Hess EV: Report of studies on juvenile arthritis. Arthritis Rheum 1977; 20 (suppl 2): 189. 40. Tyson TL, Thompson WAL, Ragan C: Marie-Strumpell in women. Ann Rheum Dis 1953: 12: 40. 41. Dequeker J. Decock T, Walravens M, Van DePutte I: A systematic survey of the HLA-B27 prevalence in inflammatory rheumatic diseases. J Rheum 1978; 5: 452. 42. Resnick D. Dwosh IL, Goergen TG: Clinical and radiographic abnormities and ankylosing spondylitis: a comparison of men and women. Radiology 1976; 119: 293.
Volume 69
Chronic Arthritis
Clinical and Roentgenographic Subset
FRANK C. ARNElT, M.D.* WILMA B. BIAS, Ph.D. MARY BETTY STEVENS, M.D. Baltimore, Maryland
From The Rheumatology Division and Immunogenetics Laboratory, Department of Medicine, The Johns Hopkins University School of Medicine and Hospital, and The Good Samaritan Hospital, Baltimore, Maryland. This study was supported by OPD-CRC Grant 5MOlRROO722-07 and a multipurpose Arthritis Center Grant lP60AM20558-01. Requests for reprints should be addressed to Dr. Frank C. Arnett, The Good Samaritan Hospital, 5601 Loch Raven Boulevard. Baltimore, Maryland 21239. Manuscript accepted March 2.1980. * Clinical Scholar of the Arthritic Foundation.
Features of a Unique HLA-B27
Previous studies of HI&B27 in children with juvenile-onset chronic arthritis have shown an association in boys with pauciarticular disease which may progress to ankylosing spondylitis. The spectrum of B27-associated disease, however, especially as it relates to arthritis persisting into adulthood, has not been fully clarified. Thus, clinical, roentgenographic, serologic and immunogenetic studies were performed in 54 patients (39 adults and 15 children) with persistent juvenile-onset chronic arthritis. All had had the onset of disease in peripheral or axial joints, and patients with typical febrile Still’s disease were excluded. Thirty-five patients (65 percent) were seronegative for both rheumatoid factor and antinuclear antibodies. HLA-B27 (BJT)was present in 20 of these 35 seronegative patients (54 percent) (p < 0.005) Four of the 20 (20 percent) had an axial onset and typical ankylosing spondylitis. Peripheral arthritis, however, dominated the course of the remaining 16 patients who had the B27 antigen. Polyarticular disease (nine patients) with “rheumatoid-like” hand deformities (eight patients) occurred primarily in female patients. In addition, sacroiliitis or spondylitis occurred in 14 and acute iritis in five. Cervical apophyseal joint fusion, especially at the level of the C2-C3, a lesion previously ascribed to juvenile rheumatoid disease, was common i@seronegative patients a:d correlated with the presence of B27 (p < 0.01) and sacroiliitis (p < 0.0005). These data suggest that the presence of B27 may mark a group of young women with a dominant peripheral and cervical spondylitic syndrome, often beginning in childhood, which mimics rheumatoid arthritis. Determining the absence or presence of the B27 antigen may be a useful test in the proper diagnosis and classification of such patients. Juvenile-onset chronic arthritis, also termed juvenile rheumatoid arthritis, is now believed to represent more than one distinct disease entity [l-4]. The diversity of dlinical presentations, patterns of articular involvement, extra-articular features and the presence or absence of rheumatoid factors (RF] and antinuclear antibodies [ANA], strongly suggest a heterogeneous group of rheumatic diseases [l-4,5,6]. The association of certain histocompatibility (HLA) antigens with different clinical subsets adds evidence of genetic heterogeneity as well [7-111. Previous studies of children have demonstrated a high frequency of HLA-B27 in boys with oligo- or pauciarticular-onset in whom more classic signs of ankylosing spondylitis may later develop [8-lo]. There are, however, few studies of adults whose disease has persisted since
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JUVENILE-ONSET CHRONIC ARTHRITIS-ARNETT
TABLE I
TABLE III
Patients with Juvenile-Onset Chronic Arthritis Classified with Respect to Serologic Markers and HLA-B27 Total
Groups Group A = B = Group A = B =
ET AL.
Patients (no.) Adults 24
35
I, Seronegative HLA-B27 positive HLA-527 negative II, Seropositive RF with or without ANA ANA alone
(20)’ (W 19
15
(12) (7)
(4) (71 4 (2) (2)
(10) (5)
39
54
TOW
Children 11
(16) (8)
15
NOTE RF = rheumatoid factor; ANA = antinuclear antibodies. l p < 0.005 for comparison of B27 in seronegative versus sero-
positive patients.
childhood to determine how the B27 antigen may influence future expression of disease. Thus, a systematic clinical, serologic and roentgenographic review coupled with HLA typing was initiated in our patients with juvenile-onset chronic arthritis, both adults and children. In this report we describe the unique clinical and roentgenographic features in these patients, many heretofore diagnosed as having rheumatoid arthritis, who appear to have a B27-associated disease. MATERIALS AND ME~ODS Patient Selection. All patients, children or adults, with a diagnosis of juvenile rheumatoid,arthritis or juvenile-onset chronic arthritis evaluated by members of this adult rheumatology division between fuly 1.1974 and December 3X1978, were reviewed per protocol. Definitions were those suggested by the JRA Criteria Subcommittee of the American Rheuma-
TABLE II
Ages of Onset, Ag& at Evaluation and Disease Duration in Patients with JuvenileOnset Chronic Arthritis I
ASeM Onset
No. GroupI, Seronegative A = B27 positive Range Mean B = 827 negative Range Mean
Group It, Seropodtlve A = RF positive Range Mean B = ANA positive Range Mean
lyr)
Ageat &sass EvaluationDuration (Yr) (Yr)
35 (20) 3-16 11.0
11-62 29.7 ’
l-52 18.7
3-16 11.3
6-38 20.2
0.25-29 10.9
4-10 10.3
9-72 19.1
0.75-58 8.8
3-16 8.2
7-38 17.6
0.5-27 9.3
(16)
19 (12)
(7)
NOTE: RF = rheumatoid factor; ANA = antinuclear antibodies.
370
Pattern of Peripheral Joint Onset of Juvenile Chronfc Arthritis by Sex
September 1980 The American Journal of Medicine
Group I, Seronegative A = B27-positive Female Male B = B27-negative Female Male Group II, Seropositlve A = RF-positive Female Male B = ANA-positive Female Male
Patients (no.1
Polyarticular’ onsst flKLf
Pauciarttculait met ino.)
10 lot
7 2
3 4
12 3
8 0
4 3
9 3
8 3
1 0
5 2
0 0
5 2
NOTE: RF = rheumatoid factor; ANA = antinuclear antibodies. l Greater than four joints affected. f Four or fewer joints affected. t Four of these B27positive males had onset in the low back rather than peripheral arthritis.
tism Association [12.13] and included (I) persistent arthritis in one or more peripheral joints for at least three months; (2)onset at age 16 or under; and (3) exclusions of other causes of arthritis in children. No attempt was made, however, to exclude juveniles whose disease had begun as an exclusively axial arthropathy and progressed to typical a&losing spondylitis (four patients]. On the other hand, patients with a typical clinical picture of the acute febrile form of juvenile rheumatoid arthritis (Still’s disease) were not included in this study [5,6,14,15]. Eight such patients were seen over the same time interval, but none had a persistent arthritis, only one had evidence of destructive changes on roentgenograms (bilateral fusion of the wrists), and previous studies have shown no association of B27 with this group [7-191. Patients were selected without regard to the presence or absence of rheumatoid factor, ANA or HLA-B27. Clinical records and roentgenograms were reviewed, and patients were recalled for study when data were incomplete. All had complete histories and physical examinations, roentgenograms of symptomatic or abnormal joints and tests for RF and ANA. HLA typing was performed in all but those who had RF, since previous studies have shown no B27 association with this group [7-lo].
Subclassification into Patient Groups. Group I-Patients seronegative for RF and ANA: A, HLA-B27 positive; B, HLA-B27 negative. Group II-Patients seropositive for A, RF with or without concomitant ANA; B, ANA alone. The pattern of onset was defined as polyarticular if greater than four joints were involved over the first six months of illness, and pauciarticular if four or fewer joints were affected, as previously suggested by Brewer et al. [X3]. Roentgenographic Methods. All patients with symptomatic cervical spine disease had lateral extension and flexion views to assess apophyseal joint fusion and subluxation of the first
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JUVENILE-ONSET CHRONIC ARTHRITIS-ARNETT
TABLE IV
ET AL.
Roentgenographic and Extra-artlcular Flndings in Patients with Juvenile-Onset Chronic Arthrltls
Roantgenographk Features Carvkal
Extra-artkular Features
No.
‘%A-like” Hands
Apophyseal Fuslon’
Cl-C2 Subluxation+
SI or sPondyll8s*
Heel PaIn
Acul lrlllsI
Chronic lrllls#
20 15
6 3
10 3
1 0
14 1
6 2
5 0
0 0
0 0
6 3
12 7
8 1
0 0
6 0
0 0
0 0
0 0
0 3
5 0
2 0
RA Nodules**
Mlcro9. nalhla++
Group I, Seronegatlve A = B = Group A = B =
B27-positive B27-negative II, Seroposltlve RF-positive ANA-positive
NOT’&: SI = sacroiliitis; RF = rheumatoid factor; ANA = antinuclear antibodies; RA = rheumatoid. p< 0.01 for association with 827. + p 5 0.0001 for association with RF. g p 5 0.0001 for association with 827. 5Ii p 5 0.01 for association with B27. p 5 0.01 for association with 827. # p
l
and second cervical vertebrae. If anteroposterior films of the pelvis suggested sacroiliac disease, additional Ferguson or oblique views of the sacroiliac joints were obtained and graded by New York Criteria (161. Only those with grade 3 or 4 disease were considered to have definite sacroiliitis. Laboratory Methods. The RF content was determined by a standard latex fixation method 1171and was considered present if the titer exceeded l/160. ANA were assessed utilizing the method of Holborow et al. [la] with mouse liver as substrate. HLA typing for A, B and C locus antigens was performed with a standard microcytotoxicity test [19]. Statistical Methods. Chi-square with Yates’ correction was used for all statistical correlations. Because the presence or absence of HLA-B27 was not determined in the patients with RF, all comparisons with B27 were performed under the assumption that these patients did not have the B27 antigen. In addition, significant associations were retested assuming a normal population frequency of 10 percent for B27 in the group
TABLE V
RESULTS A total of 54 patients was studied, 39 (72 percent] had reached adulthood, whereas 15 (28 percent) were still children. The number of patients in the predefined seronegative or seropositive groups is shown in Table I. HLA-B27 was present in 20 of the 35 (57 percent) seronegative patients (p < 0.005), 16 of whom were adults and four children (Table I]. One of the seven patients with ANA alone (group II, B) had B27. Patients with RF (group II, A] were not studied for B27. Among the 15 seronegative patients without B27, four (27 percent) had B7, an immunologically cross-reactive specificity with B27 [20] (p = NS), and four (27 percent) had BW38, an antigen found in 2 percent of our 1,000
Clinical and Roentgenographlc Characteristics of Cervical Spine Involvement In Patient Groups with Juvenile-Onset Chronic Arthritis
Csrvlcal Pain (no.)
Llmllsd CWVhXl Mo8on (M
20 15
11 (55)
12 (60)’
6 (40)
3 (20)
12 7
9 (15) 0
1 (6)§ 011
Patients (no.) Group A = B = Group A = B =
with RF. If both comparisons did not yield a value of p ? 11.05, no significance was ascribed.
I, Seronegatlve B27-positive B27-negative II, Seroposltlve RF-positive ANA-positive
FuslonC2-C3 Alone (no.)
FU8fOll C2-C3 and/or Below (no.)
4 (20)+$
6 (30)+*
2 (13)
1 (7)
1 (5) 0
0 0
0 0
6 (50) 0
Cl-C2 SUblUX-
aliom (no.)
NOT&: RF = rheumatoid factor; ANA = antinuclear antibodies. Figures in parentheses are percents. p 5 0.05 for association of limited cervical motion with 827 versus non-B27 seronegative patients. t p < 0.0005 for association between fusion of C2-C3 and/or below with limited cervical motion. $ p < 0.01 for association between fusion of C2-C3 and/or below with B27. 8 p 5 0.01 for association of limited cervical motion with 827 versus RF-positive patients. 1’p < 0.01 for association of limited cervical motion with 827 versus ANA-positive patients. l
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ET AL.
Figure 1. Roentgenograms of hand showing rheumatoid-like deformities in a 54 year old woman with onset at age 16. This patient now has complete spinal fusion and HLA-B27 (group I, A).
normal controls (corrected p < O.OOS),which is also associated with psoriatic arthritis [Zl]. None had psoriatic skin lesions. The ages of onset among the groups were similar (Table II). Forty-four patients (81 percent) were white and nine were black, only two of whom had the B27 antigen. One additional oriental patient had the B27 antigen. Sex and Pattern of Onset. There was a striking predominance of females in all groups (Table III], except for the equal sex distribution in those with the B27 antigen (B27-positives, group I, A]. Furthermore, a polyarticular mode of onset was most common in the
B27-positive females (seven of 10). Of the 10 B27-positive males, only two had a polyarticular onset whereas four had pauciarticular disease; four males had only an axial presentation [low back pain]. In the B27-negative and RF-positive groups, a polyarticular onset was most common, whereas all patients with ANA alone (group II, B) had pauciarticular disease. Clinical and Roentgenographic Features. The major clinical and roentgenographic findings among these groups are shown in Table IV. The B27-positive patients seemed to cluster together with certain unique articular and extraarticular manifestations.
Figure 2. Roentgenogram showing lateral flexion of the cervical spine in a young woman with 827 and peripheral arthritis showing fusion of the apophyseal joint between segments of the second and third cervical vertebrae (group I, A).
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JUVENILE-ONSET
A destructive peripheral polyarthritis, clinically and roentgenographically indistinguishable from rheumatoid arthritis, occurred in eight patients (six females and two males]. Symmetrical involvement of the small joints of the hands with flexion deformities of digits and fusion of wrists was prominent (Figure 1). The clinical character and roentgenographic appearance of cervical spine involvement also seemed to distinguish certain groups (Table V). Neck pain was common in both seronegative and seropositive patients; however, significant limitation of cervical extension and rotation was more common in B27-positive patients (60 percent] when compared to those w/th RF (8 percent] (p < 0.01) and ANA (0 percent] (p < 0.01). Roetgenograms of the cervical spine were available and reviewed in 51(94 percent) of the patients. Roentgenographically, fusion of cervical apophyseal joints was associated with limitation of neck motion (p < 0.0005] and with B27 (p < 0.01). Fusion between the second and third cervical vertebrae alone (Figure z), or in combination with lower segments (Figure 3)-lesions frequently ascribed to juvenile rheumatoid disease-occurred in 10 patients with B27. On the other hand, subluxation of the first and second cervical vertebrae-a lesion common to adult rheumatoid arthritis-occurred in six (50 percent] of those with RF (p ‘T 0.0001). Interestingly, of the three B27-negative patients (group I, B) with cervical spondylitis, Crohn’s disease developed in one 10 years after the onset of arthritis and another had HLA-BW38, an antigen associated with psoriatic arthritis [21]. Sacroiliitis was found in 14 B27-positive patients (six women and eight men], in six of whom (five men and one woman) syndesmophytes in lumbar and thoracic regions (spondylitis] had developed (Table IV]. Four of these patients denied having any symptoms of back pain. The presence of cervical apophyseal fusion correlated strongly with lower axial skeletal involvement (p <0.0005) (Table IV]. Heel pain with roentgenographic evidence of calcaneal periosititis was present in eight patients (40 percent] with B27 (p ‘T 0.011, whereas two seronegative, B27-negative patients had heel pain without any abnormality noted on roentgenograms (Table IV]. The type of inflammatory ocular disease (iritis) also segregated by laboratory marker (Table IV). Five B27-positive patients had had multiple episodes of acute iritis which had resulted in significant visual loss in two. Besides the correlation with B27 (p 7 O.Ol), this form of ocular disease was also associated with sacroiliitis (p 0.005). Conversely, an insidious chronic iridocyclitis resulting in visual loss occurred in three patients seropositive only for ANA (group II, B) (p 7 0.0005). A recessed mandible or micrognathia, a hallmark of juvenile arthritis, although most common in the B27 group did not statistically correlate with this marker (Table IV). Similarly, no relation to age of onset or temporomandibular joint symptoms could be found,
CHRONIC
ARTHRITIS-ARNETT
ET AL.
Figure 3. Roentgenogram showing lateral flexion of the cervical spine showing fusion of all apophyseal joints. The patient had onset of arthritis at age three and Crohn’s disease developed 10 years later. HLA-627 was absent (group I, 6).
although there was a correlation with polyarticular onset (p < 0.001). Instead, this abnormality of growth was associated with cervical apophyseal joint fusion (p < 0.01). No patients with subluxation of the first and second cervical vertebrae had micrognathia. Rheumatoid nodules were present only in five patients (10 percent), all of whom had RF (group II, A) (p < 0.0005). Comparisons with Adult-Onset Spondylitis. Because these B27-positive patients, especially the women, appeared to have an atypical spondylitic syndrome, a review of our adult patients with spondylitis was undertaken. Seven of 61 patients had been classified as having atypical spondylitis because of severe peripheral or cervical arthritis or both [Table VI). The peripheral arthritis in these predominantly young white women frequently mimicked or was diagnosed as rheumatoid arthritis despite the absence of RF. Equally striking was the finding of cervical apophyseal joint fusion indis-
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JUVENILE-ONSET
TABLE VI
Patient 1
2
CHRONIC
ARTHRITIS-ARNETT
ET AL.
Adults with Atypical Spondylitic Syndromes Characterized by Prominent Peripheral Arthritis, Cervical Spondylitis or Both, Similar to Juvenile-Onset Chronic Arthritis Associated with HLA-B27
Race and Sex
Age at Onset (vr)
Disease Duration (yr)
23
4
W,F
WI
25
22
3
WS
20
1
4
W,F
37
10
5
WS
39
3
6
W.F
27
25
7
W,M
39
3
Peripheral Joints Involved PIPS, MCPs, Ws, KS, Es, Ss, MTPs, TMJs PIPS, Ws, KS PIPS, MCPS, ws, Es, Ss, KS, As PIPS, ws
Cervical Pain Reslr
+
+
Cervical Spondylitis (level)
+
Low Back Pain Restr
-
Sacroiliitls
HLA027
+
+
C2-C3
+
+
+
+
+
+
+
+
-
C2-C5 -
+
-
-
+
+
+
+
+
-
+
-
-
-
-
-
+
+
+
+
+
-
+
+
None
+
+
PIPS. MCPs, Ws, KS, As, MTPs PIPS, MCPs, Ws, Ss, KS, As, MTPs
+
-
C2-C4 + C2-C4 -
+
-
-
NOTE: Restr = restriction; PIPS = proximal interphalangeal joints; MCPs = metacarpalphalangeal joints; Ws = wrists; KS = knees; Es = elbows; Ss = shoulders, As = ankles; MTPs = metatarsal phalangeal joints; TMJs = temporomandibular joints. C2 = second cervical vertebra; _ C3 = third cervical vertebra; C4 = fourth cervical vertebra.
tinguishable from that found in the patients with juvenile-onset chronic arthritis. HLA-B27 was present in five (71 percent]. COMMENTS Juvenile-onset chronic arthritis is a generic diagnostic term recently suggested because of the realization that juvenile rheumatoid arthritis was not one disease entity [l]. Earlier subclassifications of juvenile rheumatoid arthritis had reflected this suspected clinical heterogeneity in that they were based on different modes of presentation [Z&23]. The application of serologic markers appeared to further define subgroups. RF was most commonly found in those with polyarticular-onset, rheumatoid nodules and a bad prognosis [24-261, whereas ANA marked a group of girls with pauciarticular disease at risk for chronic iridocyclitis [27]. The genetic marker, HLA-B27, known to be strongly associated with ankylosing spondylitis and Reiter’s syndrome [28-311, was also found in 26 to 42 percent of the patients with juvenile-onset chronic arthritis [~-IO]. Those with B27 were most commonly boys with pauciarticular involvement in whom sacroiliitis or even ankylosing spondylitis later developed. It is noteworthy that in several of these series [7,9,10] there were small numbers of patients, including girls, with B27 and a polyarticular onset. Because the frequency of B27, although slightly increased over normal population frequencies, did not reach statistical significance, it could not be confidently associated with the disease process. The present study in an adult rheumatology setting focused primarily on adults who still required medical
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surveillance for a juvenile-onset chronic arthritis, often after many years. Of the 20 patients with B27-positivity, four men (20 percent) had a lower axial onset with progression to typical ankylosing spondylitis. The remaining 16 patients, however, had all presented with peripheral arthritis which persisted and was polyarticular in the majority, especially women (seven females, two males). The reason for this apparent change in disease spectrum with time is not entirely clear. It is possible, however, that many of the boys with earlier disease had shown improvement and no longer sought medical care, or had been reclassified when more typical ankylosing spondylitis became apparent. The girls, on the other hand, continued to have persistent peripheral arthritis, and the diagnosis of juvenile rheumatoid arthritis was apparently never questioned or re-examined. The validity of these observations is supported by a similar study of “juvenile rheumatoid arthritis persisting into adulthood” performed over a decade ago which also documented a high frequency of women with seronegative peripheral, cervical and low back arthritis [32]. HLA-B27 was unknown at that time and could not be applied. The majority of our B27-positive patients with childhood-onset peripheral arthritis, as well as a group of patients with adult-onset disease with similar features, were white women with a dominant peripheral and cervical articular syndrome. A deforming and destructive peripheral polyarthritis affecting in symmetric fashion the small joints of the hands and wrists and frequently other joints, clinically mimicked adult rheumatoid disease, except for the absence of nodules and RF. Lower axial skeletal complaints, although fre-
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JUVENILE-ONSET CHRONIC ARTHRITIS-ARNETT
quently present, seemed to be overshadowed by peripheral disease. Nonetheless, sacroiliitis or spondylitis was present roentgenographically in the majority. Of special interest was the type of cervical spine involvement which differed between the groups. Fusion of the apophyseal joints between segments of the second and third cervical vertebrae or below has been considered a hallmark of juvenile rheumatoid arthritis [33-361, whereas subluxation of the first cervical vertebrae on the second cervical vertebra is commonly seen in adult patients with seropositive rheumatoid arthritis [37-381. This study demonstrates that cervical apophyseal fusion is strongly associated with B27, seronegativity and sacroiliitis-all features of spondylitic rather than rheumatoid disease. On the other hand, children with RF-positive arthritis appear more likely to have subluxation of the first and second cervical vertebrae like their counterparts with adult-onset disease. Micrognathia is another well-recognized complication of juvenile rheumatoid arthritis; however, the reasons for growth retardation of the mandible remain unclear. Calabro et al. [6] have stated that it may relate to cervical spine disease, whereas other studies [39] do not confirm this impression. In the present series, micrognathia did not correlate with cervical spine disease in general, or with subluxation of the first and second
ET AL.
cervical vertebrae. There was, however, a strong association with a more specific cervical abnormality, namely, cervical apophyseal fusion. The reasons for describing these patients transcend the need to clarify disease classification. Juvenile rheumatoid arthritis is clearly a misnomer in the majority of patients with a childhood-onset chronic arthritis. The use of this diagnostic label may promote inaccurate prognostication and dictate therapy which is ineffectual, hazardous or both. In addition, in patients with spondylitis certain unique articular and extrarticular complications often develop which might go unrecognized or be inappropriately treated. Furthermore, these data support the existence of a unique form of spondylitis, usually affecting children or young adult women, in which peripheral and cervical involvement dominates the clinical picture [40-421. Roentgenographic attention to the cervical as well as the lower spine may improve diagnosis of these patients. Finally, determination of HLA-B27 in seronegative childhood-onset arthritis, regardless of the patient’s sex or number of involved joints, may provide a useful diagnostic aid. It must be emphasized, however, that proper interpretation of a positive B27 test depends upon a comprehensive clinical evaluation and, in some patients, a watchful period of time.
REFERENCES 1. Ansell BM: Chronic arthritis in childhood. Ann Rheum Dis 1978; 37: 107. 2. Schaller JG: Juvenile rheumatoid arthritis. I. Arthritis Rheum 1977; 20 (suppl2): 165. 3. Ansell BM: Juvenile chronic polyarthritis. III. Arthritis Rheum 1977; 20 (suppl2): 176. 4. Schaller JG: The diversity of JRA. A 1976 look at the subnrouus of chronic childhood arthritis. Arthritis Rheum 197?; 20.(suppl6): 52. 5. Calbro JJ. Katz RM, Maltz BA: A critical reappraisal of juvenile rheumatoid arthritis. Clin Orthop 1971; 74: 101. 6. Calabro JJ, Holgerson WB, Sonpal GM, Khoury MI: Juvenile rheumatoid arthritis: a general review and report of 100 patients observed for 15 years. Semin Arthritis Rheum 1976; 5: 257. 7. Rachelefsky GS, Terasaki PI, Katz R. Stiehm ER: Increased prevalence of W27 in juvenile rheumatoid arthritis. N Engl J Med 1974; 290: 892. 8. Edmonds J, Morris RI, Metzger AL, et al.: Follow-up study of juvenile chronic polyarthritis with particular reference to histocompatibility antigen W27. Ann Rheum Dis 1974: 33: 289. 9. Schaller JG, Ochs HD, Thomas ED, Nisperos B, Feigl P, Wedgwood RJ: Histocompatibility antigens in childhoodonset arthritis. J Pediatr 1976; 88: 926. 10. Veys EM, Coigne E, Mielants H, Verbruggen A: HLA and juvenile chronic arthritis. Tissue Antigens 1976; 8: 61. 11. Stastny P. Fink CW: Different HLA-D associations in adult and juvenile rheumatoid arthritis. J Clin Invest 1979; 63: 124. 12. Brewer EJ, Bass JC. Cassidy JT, et al.: Criteria for classification of juvenile rheumatoid arthritis. Bull Rheum Dis 1973; 23: 712. 13. Brewer EJ, Bass JC, Baum J, et al.: Current proposed revision of JRA criteria. Arthritis Rheum 1977; 20 (suppl2): 195. 14. Still GF: On a form of chronic joint disease in children. Med
Chir Trans 1897; 80: 1. 15. Baum J, Baum ER: George Frederic Still and his account of childhood arthritis-a reappraisal. Am J Dis Child 1978; 132: 192. 16. Gofton JP: Report from the subcommittee on diagnostic criteria for ankylosing spondylitis. In: Bennet RH, Wood PNH. ed. Ponulation studies of the rheumatic diseases. Amsterdam: Bxcerpta Medica Foundation, 1968; 456. 17. Sinner IM. Plotz CM: The latex fixation test. I. ADDlication tothe serologic diagnosis of rheumatoid arthritis. ‘Am J Med 1956; 21: 888. 18. Holborow EJ, Weir DM, Johnson GD: A serum factor in lupus erythematosus with affinitv for tissue nuclei. Br Med 11957: 2: -732. 19. Amos DB, Bashir H, Boyle W, MacQueen M, Tiilikainen A: A simple microcytotoxicity test. Transplantation 1969; 7: 220. 20. Arnett FC. Hochbere MC. Bias WB: Cross-reactive HLA antigens in B27-negitive Reiter’s syndrome and sacroiliitis. Johns Hopkins Med J 1977; 141: 193. 21. Espinoza LR, Vasey FB, Oh JH, Wilkinson R, Osterland CK: Association between HLA-BW38 and peripheral psoriatic _ arthritis. Arthritis Rheum 1978; 21: 72.. _ 22. Calabro JJ, Marchesano JM: Juvenile rheumatoid arthritis. N Engl J Med 1967; 277: 696,746. 23. Bywaters EGL: Categorization in medicine: a survey of Still’s disease. Ann Rheum Dis 1966: 26: 185. 24. Bianco NE, Panush RS, Stillman JS, Schur PH: Immunologic studies of juvenile rheumatoid arthritis. Arthritis Rheum 1971;14:685. 25. Schaller J, Wedgewood
RJ: Juvenile rheumatoid arthritis: a review. Pediatrics 1972; 50: 940. 26. Goel KM, Shanks RA: Follow-up study of 100 cases of juvenile rheumatoid arthritis. Ann Rheum Dis 1974; 33:25. 27. Schaller JG, Johnson GD, Holborow EJ, Ansell BM, Smiley WK: The association of antinuclear antibodies with the
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28. 29. 30. 31. 32. 33. 34.
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